2-alkyl-3, 3-diphenyl-propen-(2)-yl-amines and salts thereof



United States Patent 3,345,411 2-ALKYL-3,3-DIPHENYL-PROPEN-(2)-YL-AM1NESAND SALTS THEREOF I Werner Heinrich and Walter Heigel, Ludwigshafen(Rhine), Germany, assignors to Gehr. Giulini G.m.b.H., Ludwigshafen(Rhine), Germany, a corporation of Germany No Drawing. Filed Nov. 19,1963, Ser. No. 324,824 Claims priority, application Germany, Nov. 23,1962,

G 36,467 23 Claims. (Cl. 260-570) This invention relates to propylaminederivatives and provides novel compounds of this class, new methods forproduction of such compounds, and methods for use of such compounds.

This application is a continuation-in-part of application Ser. No.231,018, filed Oct. 16, 1962, which in turn is a continuation-in-part ofapplication Ser. No. 54,542, filed Sept. 7, 1960, both now abandoned.

The novel compounds of the invention are according to the followingformula:

wherein they diminish or eliminate the undesirable depressive sideelfects of morphine on respiration.

R is preferably ethyl, propyl or butyl. With respect to the salts ofthese preferred compounds, the disclosure here inafter with reference tosalts of the vasopressor agents of the invention apply, and with respectto the amines,

these preferences apply to each the secondary and primary derivatives.

The invention further utilizes compounds of the following formula: I I Iwherein R, R and R are as above. These alcohol-amines are useful in theproduction of compounds of Formula I.

The invention further provides the method of providing a vasopressoreffect. This is accomplished by administering a therapeutic amount of acompound according to Formula I.

Of the compounds according to Formula I, preferred ice chlorides.Specific compounds within this group are: 2- ethyl3,3-diphenyl-propen-(2)-yl-amine, and cyclohexyl-[2-ethyl-3,3-diphenyl-propen-(2)-yl]-amine. A compound to be accordedspecial mention in this group is cyclohexylwherein R is hydrogen, loweralkyl, or cyclohexyl. This group includes the medicinally acceptablesalts of the compounds of Formula III.

In Formula In Where R is of the type conventionally present as asu-bstituent in organic amino compounds designed for therapeuticapplication, and preferably'contains not more than about 6 carbon atoms.R can be for example, methyl, butyl, ethyl, propyl, isopropyl, isobutyl,secondary butyl, isoamyl, heXyl, isohexyl, cyclohexyl and similar orrelated radicals.

Thecompounds of Formula III can be used in the form of thehydrochloride, but preferably are used as salts, e.g. acid additionsalts. The salts are crystalline solids which are soluble in water andtherefore constitute an advantageous embodiment of this invention.

The organic bases of the type shown in Formula III form salts with avariety of inorganic and organic acids conventionally used fortherapeutic application of organic C5115 R (IV) wherein R is an alkylgroup containing 2 to about 8 carbon atoms, especially 4 to about 8car-bon atoms. These compounds can be in the form of their medicinallyacceptable acid addition salts. Particularly preferred compounds withinthis group are those in which R is.n-butyl, n-pentyl, or n-octyl. Whatis said herein-with reference to salts ofFormula I, applies also tosalts of Formula IV.

Included within this group of Formula IV is 2-propyl-3,3-d-iphenyl-propen (2")-yl-amine. This compound has been found wellsuited to the purposes of the invention. j Another preferred group ofcompounds withinthe compounds of Formula I is the group represented bythe following formula:

-Q O=CCHzNHz our,

in which R is lower alkyl, lower alkoxy or chloro. These compounds canbein the form of their medicinally acceptable salts. Particularcompounds of this group which have been found well suited for thepurposes of the invention are the compounds wherein R is chloro, methylor methoxy. What has been said herein with reference to salts ofcompounds of Formula I, applies also to salts of compounds of Formula V.

Compounds according to Formula I can be produced by hydrogenatingcompounds of the formula:

wherein the substituents are as is described with reference to FormulaI, to produce the corresponding alcohol-primary amine. If a secondaryamine according to Formula I is to be produced, the said alcohol-primaryamine can be reacted with an alkyl or cycloalkyl carbonyl compound underreducing conditions for the desired alkylation. The product propeneamine can then be obtained by dehydrating the alcohol-primary, or-secondary amine, as the case may be.

The hydrogenation of the nitrile can be a catalytic hydrogenation. Adesirable catalyst for the reaction is platinum, and the reaction ispreferably carried out in a solvent for the nitrile, for example aceticacid or methanol.

The dehydration of the alcohol-amine can be carried out by the known andconventional dehydrating methods,

and preferably employing as dehydrating agent gaseous hydrogen chloridewith the alcohol-amine in solution. Solvents such as acetic acid can beused, and the dehydration can be effected by heating the solution underreflux for a time sufficient to complete the dehydration.

Where, in accordance with Formula I, halogen is present, thehydrogenation is with lithium aluminum hydride rather thancatalytically. In such cases the nitrile containing chloro substituentcan first be dehydrated to form an acrylonitrile derivative and thisderivative can be hydrogenated with lithium aluminum hydride to form thepropene-primary amine.

A further feature of the invention is provision of a process for theproduction of primary amines. Thus, the invention provides forproduction of primary amines such as amines of Formula I wherein R ishydrogen, and the substituents on the phenyl groups are hydrogen, alkyl,or alkoxy, or hydrogen or alkyl. The procedure involves catalyticallyhydrogenating the corresponding Z-hydroxypropionitrile to form therefromthe corresponding alcoholprimary amine, and dehydrating thealcohol-primary amine to form the product primary amine.

Where the primary amine to be produced includes halogen substituents oneither or both of the phenyl groups, the corresponding2-hydroxypropionitrile can be dehydrated to produce the correspondingacrylonitrile, and the acrylonitrile can be hydrogenated to form theprimary amine.

Another feature of the invention is the provision of a process forproduction of secondary amines. Thus, there can be produced compoundsaccording to Formula I wherein R is lower alkyl or cyclohexyl, and thesubstituent on the phenyl group is of the group hydrogen,

lower alkyl, lower alkoxy, and chloro, or of the group hydrogen, loweralkyl, or lower alkoxy, or of the group hydrogen or lower alkyl. In thisprocedure, the corresponding alcohol-primary amine, wherein the hydroxygroup of the alcohol is in the 3-position, is contacted with an alkyl orcycloalkyl carbonyl compound under reducing conditions to produce thecorresponding alcoholsecondary amine, and the alcohol-secondary amine isdehydrated to produce the secondary amine product.

Further details of preparation of compounds of the invention are set outbelow.

COMPOUNDS OF FORMULA III Compounds of this invention can be preparedutilizing the step of catalytically hydrogenatingl-ethyl-Z-hyd-roxyreaction is preferably carried out in a solvent forthe nitrile, for example acetic acid or methanol.

The 1-ethyl-2-hydroxy-2,2-diphenyl-propionitrile, which is necessary asbasic product, is obtained by condensation of benzophenone andbutyronitrile, which was proposed by Lettre.

The 2-ethyl-3,3-diphenylpropen-(2)-yl-amine is prepared by dehydrationof the 2-ethyl-3-hydroxy-3,3-diphenylpropylamine. The dehydration iscarried out by the known and conventional dehydrating methods, andpreferably there may be employed as dehydrating agent gaseous hydrogenchloride with the 2-ethyl-3-hydroxy-3,3- diphenylpropylamine insolution. As solvent for the 2- ethyl-3-hydroxy-3,3-diphenylpropylamine,acetic acid can be used. The dehydration is preferably carried out byheating the solution under reflux for a time sufficient to complete thedehydration.

The mono-alkylated derivatives of the hydroxylated compound are preparedby reacting the compound containing a primary amino group with an alkylor cycloalkyl carbonyl compound under reducing conditions, andpreferably the alkylation is achieved by catalytic hydrogenation of thefree base in the presence of carbonyl compounds. Thus, in accordancewith the invention, alkylation of the 2 ethyl 3hydroxy-3,3-diphenyl-propylamine is carried out and thereafter themono-alkylated 2-ethyl-3- hydroxy-3,3-diphenyl-propylamine is subjectedto dehydration to thereby obtain the mono-alkylated 2-ethyl-3,3-diphenyl-propene-amine.

Alternatively, the mono-alkylated derivatives may be obtained byreacting the 2-ethyl-3-hydr-oxy-3,3-diphenylp-ropylamine with carbonylcompounds to form the corresponding 1,3-oxazine and, through catalytichydrogenation, to split the 1,3-oxazine to form the amino alcohol.

EXAMPLE 1 Preparation of 1-ethyl-2-hydroxy-2,Z-diphenylpropio'nitrile54.6 g. of benzophenone and 20.7 g. of butyronitrile are dissolved in400 ml. of absolute ether. 16 g. of sodium amine powder are added andthe mixture is boiled for 7 hours at a temperature of 40 C. underreflux. Thereafter, the solution is given into 500 ml. of ice/water andstirred for 5 min. The reaction product separates at once in acrystalline form (the raw yield amounts to 66 g.=88%) which isrecrystallized by means of benzene with a loss of 20%. The melting pointthereby obtained is 162 C.

. EXAMPLE 2 Preparation of Z-ethyZ-S-hydroxy-3,3-diphenylpropylamine 10g. of 1-ethyl-2-hydroxy-2,2-diphenyl-propionitrile are dissolved in 200ml. of methanol. 10 ml. of acetic acid are added to the mixture, and themixture is hydrogenated in the presence of platinum as catalyst. Afterthe hydrogen uptake or consumption has ceased, the reaction isinterrupted, the catalyst is filtered off and the filtrate is evaporatedin vacuo to dryness. The residue is dissolved in water, and, after theaddition of one ml. of hydrochloric acid, the solution is extracted withether. The acidified ether-phase is discarded. The aqueous phase is madealkaline with ammonia, whereby the base crystallizes out. The crystalsare recovered and crystallized from methanol. The melting point of the2-ethyl-3-hydroxy-3,3-

dip-henylpropyl-amine thereby obtained is 132 C.

EXAMPLE 3 Preparation ofZ-ethyl-3,3-diphenyl-pr0pen-(2)-ylamine-hydrochloride 5 g. of2-ethyl-3-hydroxy-3,3-diphenylpropylamine are dissolved in 50 ml. ofacetic acid. Gaseous hydrogen chloride is passed through the solutionfor 10 minutes, and thereafter the solution is boiled for one hour underreflux. The solution is then distilled to dryness. The residue isdissolved in water and the acidified solution EXAMPLE 4Cyclohexyl-[Z-ethyl-3-hydr0xy-3,3-diphenyl-pr0pyl] amine 6 g. of2-ethyl-3-hydroxy-3,3-diphenyl-propylamine are dissolved in 200 ml. ofmethanol. 10 ml. of freshly distilled cyclohexanone are added to thesolution and the solution is hydrogenated'in the presence of a platinumcatalyst. The hydrogen consumption takes place very quickly. Thecatalyst is filtered oif and the filtrate concentrated to dryness. Theresidue is taken up in dilute hydrochloric acid and extracted withether. The hydrochloride salt Which is partially recovered from theether phase, is crystallized out from methanol ether. The crystalsthereby obtained have a melting point 'of 180-182" C. The Water phase ismade alkaline with ammonia and thereafter extracted with ether. Afterdrying over sodium sulfate, the ether extract is subjected todistillation. The residue thereby obtained recrystallized from a mixtureof acetone and water in the ratio of 2:1. The base thus recovered has amelting point of 7880 C.

EXAMPLE 5 3.37 g. of cyclohexy-[2-ethyl-3-hydroxy-3,3-diphenylpropylJ-amine are dissolved in 50 ml. ofacetic acid and gaseous hydrogen chloride is passed through the solutionuntil the reaction mixture is strongly acidic. The mixture is heated fortWo hours in a boiling water bath. The acetic acid solution isthereafter distilled under vacuo to dryness. The residue is dissolvedtwice in 50 ml. portions of methanoL and each time the solution isevaporated to dryness. The final residue is dissolved in a small amountof methanol and the hydrochloride salt crystallized out by addition ofabsolute ether. The crystalline substance thereby obtained has a meltingpoint of 212215 C.

Compounds havingalkyl substituents on the amino group other than theinstances disclosed in the examples may be obtained by carrying out theforegoing experiments using in the alkylation reaction other alkylcompounds, as for example methyl, pentyl, hexyl, butyl, diethyl, etc. Itis furthermore possible to prepare, in lieu of hydrochlorides,corresponding salts of other acids by contacting the base-in the form ofits solution with an acid as forexample hydrobromic, hydroiodic,phosphoric,

citric, oxalic, in place of the hydrochloric acid, until the reactionmixture-is strongly acidic. The said solution may .have [to beconcentrated somewhat for crystallization, upon chilling, to occur.

COMPOUNDS OF FORMULA IV These compounds can be made by reactions as areare dissolved in 350ml. glacial acetic acid, 0.5 g. platinum catalystare added and then. hydrogenated. After -co'mpleted hydrogenation, thecatalyst is filtered Off, and

the filtrate is evaporated in vacuum to dryness. The residue is treatedwith water, treated with hydrochloric acid until the acid reaction,filtered off from the undissolved materiaL and extracted with ether. Theaqueous phase is 6 made alkaline with ammonia solution, extracted withether and the ether part dried via sodium sulfate. After distilling offof the ether the 2-n-butyl-3-hydroxy-3,3-diphenyl-propyl-amine isobtained. Melting point: 84 C.

EXAMPLE 6b 2-n-butyl-3,3-diphenyl-propen-(2 -yl-amine-hydr0- chlorideEXAMPLE 7a Z-n-pentyl-3-hydr0xy-3,3-diphenyl-propyl-amine Throughhydrogenation of l-n-pentyl-2-hydroxy-2,2- diphenyl-propionitrile oneobtains the 2-n-pentyl-3-hydroxy-3,3-diphenyl-propyl-amine in analogousmanner according to Example 6a. Melting point: 57 C.

EXAMPLE 7b 2-n-pentyl-3,3-diphenyl-prop en- (2 -yl-amine-hydro. chlorideThe solution of 9.5 g. 2-n-pentyl-3-hydroxy-3,3-diphenyl-propyl-amine inml. glacial acetic acid is saturated with hydrogen chloride andsubsequently heated for three hours to 100 C. The acetic acid isdistilled olf in vacuum, and the 2-n-pentyl-3,3-diphenyl-propen-(2)-yl-amine-hydrochloride remaining is recrystallized from benzene. Meltingpoint: 138140 C.

EXAMPLE 8a 2-n-0clyl-3-hydroxy-3,3-diphenyl-propyl-amine Throughhydrogenation of 1-n-octyl-2-hydroxy-2,2- diphenyl-propionitrile oneobtains the 2 n-octyl-3-hydroxy-3,3diphenyl-propylamine in analogousmanner according to Example 6a. Melting point: 88 C.

EXAMPLE 8b 2-n-0ctyl-3,3-diphenyl-pr0pen-(2 -yl-amine-hydrochloride Thesolution of 38.5 g. 2-n-octyl-3-hydroxy-3,3-diphenyl-propyl-amine in 200ml. glacial acetic acid is saturated with hydrogen chloride gas andsubsequently heated for three hours to 100 C. The crystals of2-noctyl-3,3-diphenyl-propen-(2) yl amine-hydrochloride remaining behindafter distilling off of the acetic acid in vacuum, are washed-out withabsolute ether. Melting point: 157 C.

The comments made above with respect to the examples under Formula IIIas to substitutions in the examples, applyto the foregoing examples ofcompounds of Formula IV.

COMPOUNDS OF FORMULA V These compounds can be'produced in a manneranalogous to production of compounds of Formula III, that is, throughhydrogenation of 1-ethyl-2-hydr0Xy-2,2-di

aryl-propionic-nitrile and separation of water. In the cases in which ahalogen substitution exists, hydrogenation can be by means of lithiumaluminum hydride. In all other cases, the reduction can be effectedcatalytically. In these 'reactions, there is formed a mixture of twocis-transforms.

- EXAMPLE 9 .2 ethyl-3-phenyl-3-(p-methyl-phenyl)-propen- (2)- lyl-amine-hydrochloride 13.3 g. 1-ethyl-2-hydroxy-2-phenyl 2(p-methylphenyl)-propionic nitrile are dissolved in 400 ml. glacialacetic acid, 200 mg. platinum catalyst are added and subsequentlyhydrogen is introduced. After completion of hydrogen absorption, onefilters off from catalyst, and the filtrate is evaporated in vacuumuntil dry. The residue is dissolved in water, treated with hydrochloricacid until the acid reaction, filtered off from the residue, and thefiltrate added drop by drop into 20% soda lye. Therein the2-ethyl-3-hydroxy-3-phenyl-3 (p-methyl phenyl)- propyl-amineprecipitates. Melting point: 88-90 C.

4.8 g. 2-ethyl-3-hydroxy-3-phenyl3-(p-methyl-phenyl)- propyl-amine aredissolved in 50 ml. glacial acetic acid. This solution is saturated withhydrogen chloride gas and subsequently heated for 3 hours to 100 C. Theacetic acid is distilled off in vacuum. The residual crystals aredissolved in methanol and the 2 ethyl 3 phenyl-3-(pmethylphenyl)-propen-(2)-yl-amine hydrochloride precipitated through additionof absolute ether. Melting point: 223-225" C.

EXAMPLE l 2-ethyl-3-phenyl-3- (p-methoxyphenyl) -pr0pen-(2yl-amine-sulfate Through hydrogenation of 1-ethyl-2-hydroxy-2-phenyl-2-(p-methoxy-phenyl)-propionic nitrile one. obtains the 2-ethyl-3-hydroxy-3-phenyl-3-(p-methoxyphenyl) propylamine in the mannerdescribed in Example 9. Melting point: 148 C.

Into a solution of 4.2 g. 2-ethyl-3-hydroxy-3-phenyl-3-(p-methoxyphenyl)-propyl-amine one introduces for 25 minutes dryhydrogen chloride gas and subsequently heats for 2 /2 hours to 100 C.;thereafter, the material distilled until dry. The residue is dissolvedin water, made alkaline with diluted soda lye, and then extracted withether. The ether part is dried with sodium sulfate, the ether distilledoff, and the thus obtained 2-ethyl-3-phenyl-3-(p-methoxyphenyl)-propen-(2)-yl-amine converted into its sulfate. Thesubstance melts at l45165 C.

EXAMPLE 1 1 2-eth'yl-3-ph enyl-3- p-chlorophenyl -pr0pen- (2 -ylamine-hydr0chl0ride To a hot solution of 16.3 g. l-ethyl-2-hydroxy-2-phenyl-2-(p-chlorophenyl)-propionic-nitrile in 300 ml. absolute benzene, thereis very quickly added 20 g. phosphoruspentoxide. The reaction mixture isboiled for 45 minutes under reflux, the benzene solution decanted, andthe residue is twice boiled-out with each 100 ml. absolute benzene.After distilling off of the benzene, there remains thel-ethyl-2-phenyl-2-(p-chlorophenyl)-acrylo-nitrile in almostquantitative yield as yellowish oil.

A solution of 5.4 g. 1 ethyl-2-phenyl-2-(p-chlorophenyl)-acrylo-nitrilein 20 ml. absolute ether is added drop by drop within half an hour to asuspension of 0.76 g. lithium aluminum hydride in 100 ml. absolute etherunder ice-cooling and stirring, so that the temperature does not riseabove 5 C. The reaction mixture is still further stirred for half anhour and then treated, successively, with 0.8 ml. water, 0.6 ml. sodalye, and 2.8 ml. water. The yellow-colored ether solution is thendecanted from the granular precipitate, and this is then washed threetimes with 30 ml. absolute ether. The 2-ethyl-3-phenyl-3-(p-chlorophenyl) propen-(2)-yl-amine present in theether solution is isolated as hydrochloride. Melting point: 208-211 C.

As noted above, with reference to compounds of Formula III, in the caseof the compounds of Formula V various acid addition salts of thecompounds can be provided.

3-PROPYL DERIVATIVE OF COMPOUNDS 0]? FORMULA III Through hydrogenationof 1-propyl-2-hyd-roxy-2,2-diphenyl-propionic-nitrile and subsequentseparation of water from the 2-propyl-3,3-diphenyl-3-hydroxy-propyl-.arnine formed, the 2-propyl-3,3-diphenyl-propen-(2)-yl- '8 amine can beobtained. The starting material for production of the 2-propylderivatives can be obtained in a manner analogous to the manner in whichthe starting material for the compounds of Formula III is obtained.

EXAMPLE l2 2-pr0-pyl-3,3-diphenyl-propen (2) yl-amine-hydrochloride 13.1g. l-propyl-2-hydroxy 2,2 diphenyl-propionicnitrile are dissolved in 400ml. glacial acetic acid, 200 mg. platinum catalyst are added, andsubsequently hydrogen is introduced. After hydrogen absorption ceases,the catalyst is filtered off, and the filtrate evaporated in vacuumuntil dry. The residue is dissolved in water, treated with hydrochloricacid until acid reaction, the residue is filtered off, and the filtrateadded drop by drop into 20% soda lye. The precipitated2-propyl-3,3-diphenyl-3-hydroxypropyl-amine is recovered. Melting point:l08-l10 C.

4.8 g. 2-propyl-3,3-diphenyl 3 hydroxy-propyl-amine are dissolved in 50ml. glacial acetic acid. This solution is saturated with hydrogenchloride gas and subsequently heated for 3 hours at C. The acetic acidis distilled off in vacuum. The crystals remaining behind are dissolvedin methanol and the 2-propyl-3,3-diphenyl-propen- (2)-yl-aminehydrochloride is precipitated through addition of absolute ether.Melting point: 213-215 C.

What is said above with reference to salts of the compounds of FormulaIII, applies as well to the salts of the 2-propyl derivatives.

Utility data The compounds of the invention are substantially moreeffective than the corresponding 2-methyl derivatives. This can be'demonstrated by tests on anesthetized animals to which the Z-methylderivative and a 2-ethyl derivative have been administered. Furtherinformation on utility follows.

COMPOUNDS OF FORMULA III The following details were found byexperimenting with 2-ethyl-3,3-diphenyl-propen (2)-yl-aminehydrochloride on animals:

(1) Acute toxicity DL 50, white mouse, i.v. 35.5 mg./kg.

DL 50, white mouse, p.o. 87.5 mg./kg.

DL 50, white mouse, s.c. approx. 100 mg./kg. DL 50, white rat, p.o. 183mg./kg.

(2) Chronic toxicity White rat, per os 18.3 mg./kg. pro die, 20 animals:During a 30 days feeding body Weight and general behavior normal. Notoxic signs. Action of erythrocytes and leucocytes within physiologicallimits. Macroscopic and microscopic no organic conditions.

(3) Picture of actions For the most part chronic convulsions with point.of action on motor brain centers; besides tonic components ofconvulsion (stimulative effect) vasomotor center, breath center, mainlycentrally conduced increase of blood pressure, central excitation.

(4) The efiect on the blood pressure in cats under chl0-ralose-urethane-anaesthesia 0.5 rug/kg. i.v.: increase of blood pressureof 40-60 mm. Hg, effective for 6-8 minutes;

0.1 mg./kg. i.v.: increase of blood pressure of 30-50 mm. Hg, effectivefor about 5 minutes;

1 mg./kg. i.v.: increase of blood pressure of 45-60 mm. Hg, with longerefficiency;

2 mg./kg. i.v.: increase of blood pressure of 50-60 mm.

Hg, with long efiiciency.

With normal or reduced initial blood pressure the hypertensive effect isstronger than with an increased initial blood pressure.

() Efiect on the experimentally condu cec l circulatory collapse in cats(a) Circulatory collapse by Evipan-Sodium' continuous infusion:

0.1-2.0 mg./kg. i.v.: strong hypertensive efiect for a prolonged time.(b) Circulatory collapse by acetylcholine continuous infusion:

0.1-2.0 mg./kg. i.v.: with long efiiciency.

(6) Effect on the breathing in narcotized cats 0.1-2.0 mg./kg. i.v.:strong stimulation of breathing.

(7) Efiect on the heart (a) Frog, in situ perfused according toBiil'bring.

0.1 mg. percent (1:1,000,000): no change of frequency and minute volume0.4 mg. percent (1:250,000): no influence on frequency and minute volume1 mg. percent (1:100,000): decrease of ume with constant frequency. 7(b) ECG in guinea-pigs: Doses of 0.63-2.0 mg./kg. cause no significantchange in ECG apart from a temporary decrease of frequency. 7

stronger hypertensive effect minute vol- (8) Stimulative effect inrabbits under urethane anaesthesia r 4 0.1-2.5 mg./kg. i.v.: strongstimulative efl ect. (9) Eflect on the breathing of rabbits undermorphine amine has a duration of 30-40 minutes on the blood 7 pressureof the cat in urethane chloralose narcosis, while 0.5 mg./kg. of2-butyl-3,3-diphenyl-propen-(2)-yl-amine has a duration of upto 4 hours.COMPOUNDS OF FORMULA V These compounds are especially preferred sincethey have an especially pronounced eifect on blood pressure and thiseffect is particularly long-lasting." i

Effects on the blood pressure of the cat under urethane chloralosenarcosis for compounds of Formula V, as

follows, were noted.

2-ethyl-3-phenyl 3 (p-chlorophenyl)-propen-(2)-ylamine as hydrochloride,gluconate and methanesulfonate:

1 mg./kg. i.v.: blood pressure increase of 40-50 mm.

Hg, lasting about 30-40 minutes;

2 mg./kg. i.v.: blood pressure increase of 60 mm.

Hg, lasting about 2-4 hours;

3 rug/kg. i.v.: blood pressure increase of 60-80 mm.

Hg, lasting about 4 hours and longer.

For lower starting blood pressure the blood pressure increase effect isstronger and lasts longer than in normal or high starting bloodpressure.

1-(3-hydroxyphenyl)-1-hydroxy 2 N ethylaminoethane-hydrochloride of thestructural formula Q-ouon-oumnmm-uor 1 ling/kg. i.v.: blood pressureincrease of about 20 mm.

. 2 mg./kg. i.v.: blood pressure increase 10 'Hg, lasting about 4-8minutes;

of 20-30 mm. Hg, lasting about 4-8 minutes; 3 mgJkg. i.v.: bloodpressure increase Hg, lasting about 4-8 minutes; 4 rug/kg. i.v.: bloodpressure increase Hg, lasting about 4-8 minutes.

ephedrine:

1 mg./kg. i.v.: blood pressure increase Hg, lasting about 30-40 minutes;

mg/kg. i.v.: 'blood pressure increase Hg, lasting about 30-40 minutes;

3 mg./kg. i.v.: blood pressure increase Hg asting about 30-40 minutes.

In all cases, the starting blood pressure was about the same and was'between and Hg.

PRoPYL DERIVATIVES OF COMPOUNDS 0F" FORMULA III Compounds of Formula IIIhaving a propyl group in the 2-position instead of an ethyl group, areof particular interest because of their long-lasting blood pressureelfect.

Effects as folows were noted for the blood pressure of the cat inurethane chloralose narcosis. v

2-propyl-3,3-diphenyl-propen (2) yl amine as hydrochloride, gluconateand rnethane-sulfonate:

of 40-60 mm.

of 40-60 mm.

of 20-40 mm.

2 of 40-50 mm.

of 40-50 mm.

@CHOH-CEIaNHCzHsHCI I OH 1 :mg./kg. i.v.: blood pressure increase ofabout 20 mm.

Hg, lasting about 4-8-minutes; I r V 2 rug/kg. i.v.: blood pressureincrease of 20-30 mm.

Hg, lasting about 4-8 minutes;

3' nig'Jkg. i.y.: blood pressure increase of 40-60 rnm Hg.lasting-about4-8 minutes; i 1

. 4 mg./kg. i.v.z blood'pressure increase of 40-60 mm.

Hg, lasting about 4-'-8 minutes.-

The, effect of ephedrine is as reported above for compounds of FormulaV. In allicases, the starting blood pressure was about the same and wasbetween 80 and 100 mm. Hg.

Compositions The compounds in accordance with the invention may be givenin dosage form hypodermically or intramuscularly in the form of HClsalt, or in the form of their salts in isotonic physiologicallyacceptable solutions, as for example water saline or peanut oil.Locally, they may be used in solution as a spray and in ointment.

The exact dosage in each instance is entirely dependent on the eifectsought to be achieved, the mode of administration employed and thedegree of caution which must 'be observed. Dosage can be, for example,15 mg. for parenteral administration. In any instance, there is employedat least that amount of the compound, i.e. active agent, necessary toproduce the desired physiological elfect, but less than that amountproducing an undesired toxic etfect.

The compounds of the invention, as can be readily appreciated, alsoconstitute valuable tools for use in medical research, as for instancein connection with animal experiments and in particular in the study oftheir elfect on the blood pressure by stimulating the contraction of themuscular tissue of the capillaries and arterioles.

What is claimed is: 1. Compounds of the formula:

(a) R is alkyl having 2 to 8 carbon atoms; (b) R is selected from thegroup consisting of hydrogen, lower alkyl and cyclohexyl; (c) R isselected from the group consiting ofhydrogen,

lower alkyl, lower alkoxy and chlorine; and medicinally acceptable saltsthereof. 2. Compound according to claim 1, ethyl.

3. Compound propyl.

.4. Compound according to n-butyl.

5. Compound n-pentyl.

6. Compound n octyl.

7. Compound according to claim 1, wherein R and R is each hydrogen.

8. Compounds of the formula:

Q (III) wherein R is selected from the group consisting of hydrogen,lower alkyl, and cyclohexyl, and medicinally acceptable salts thereof.

9. Compounds according to claim 8, wherein R is cyclohexyl.

10. The hydrochloride of a compound according to wherein R according toclaim 1, wherein R is claim wherein R is according to claim wherein R isaccording to claim wherein R is claim 8.

11.- 2-ethyl-3,3-diphenyl-propen-(2)-y1-amine.

12. Cyclohexyl-[2-ethy1-3,3-diphenyl-propen-(2) -yl] amine.

13. Cyclohexyl-[2-ethyl-3,3-diphenyl-propen-(2) yl] amine in the form ofa medicinally acceptable salt with a member selected from the groupconsisting of hydrochloric, hydrobromic, and hydroiodic acid.

14. Compounds of the formula:

CaHs (IV) wherein R is an alykyl radical containing 2 to about 8 carbonatoms, and medicinally acceptable salts thereof.

15. Compounds according to claim 14, wherein R is n-pcntyl.

16. Compound according to claim 14, wherein R is !'1butyl.

17. Compound according to claim 14, wherein R is n-octyl.

18. The hydrochloride of a compound according to claim 14.

19. 2-propyl-3,B-diphenyLprOpen-(Z)-yl-amine and medicinally acceptablesalts thereof. 20. Compounds of the formula:

O=CCHNI-I,

in which R is selected from the group consisting of lower alkyl, loweralkoxy, and chlorine, and medicinally acceptable salts thereof.

21. 2-ethyl-3-phenyl-3-(p-chlorophenyl)-propen (2) yl-amine andmedicinally acceptable salts thereof.

22. 2-ethyl-3-phenyl-3-(p-methylphenyl)-propen- (2) yl-amine, andmedicinally acceptable salts thereof.

23. 2-ethyl-3-phenyl-3-(p-methoxypenyl)-propen-(2) O yl-amine andmedicinally acceptable salts thereof.

References Cited UNITED STATES PATENTS 2,681,934 6/1954 Hodge 260-5702,705,245 3/1955 Norton 260570 3,056,726 10/ 1962 Marsh 167-65 3,057,78010/ 1962 Shapiro 16765 FOREIGN PATENTS 525,752 6/1956 Canada.

627,139 7/1949 Great Britain. 811,659 4/1959 Great Britain.

OTHER REFERENCES Kjaer et al., A-cta Chimica Scan, vol. 5, pp. 1145-501951 Lettre et al., Ann., vol. 603, pp. 189-99 (1957). White et al.,Brit. Jour. PharmacoL, vol. 6, pp. 560-71 (1951).

CHARLES B. PARKER, Primary Examiner.

R. V. HINES, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,345,411 October 3, 1967 Werner Heinrich et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

In the heading to the printed specification, lines 9 and 10, for"Claims-priority, application Germany, Nov. 23, 1962, (3 36,467" read"Claims priority, applications Germany, G 27,898, September 8, 1959;Germany, G 34,027, January 16, 1962; Germany, G 34,038, January 17, 1962and Germany, G 36,467, November 23, 1962 column 11, the formula in claim14 should appear as shown below instead of as in the patent:

Signed and sealed this 10th day of September 1968.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J. BRENNER Attesting Officer Commissionerof Patents

1. COMPOUNDS OF THE FORMULA: